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Triple-Negative Breast Cancer Treatment Hints Drawn From Single-Cell Study

NEW YORK – A new single-cell transcriptomic analysis has defined four expression-based stromal cell subtypes within the microenvironment of triple-negative breast cancer (TNBC), an aggressive form of the disease that lacks enhanced expression of estrogen, progesterone, or HER2 receptors.

"[W]e searched for new potential targets for therapy by analyzing the individual cells inside triple negative breast tumors," first author Sunny Wu, a research assistant in senior author Alexander Swarbrick's translational breast cancer research and tumor progression lab at the Garvan Institute of Medical Research, said in a statement. "This includes not only the cancer cells themselves, but also the surrounding host cells, such as immune and connective tissue cells, which can be thought of as the cancer 'ecosystem' that supports a tumor to grow and spread."

The team's findings — one piece of a Breast Cancer Cell Atlas project aimed at sequencing more than a million individual breast cancer-related cells — were published in a paper in EMBO Journal on Thursday.

There, Wu, Swarbrick, and their colleagues outlined the single-cell RNA sequencing strategy they used to assess nearly 24,300 individual cells from biopsy samples for five individuals with TNBC, leading them to two cancer-associated fibroblast and two perivascular-like stromal clusters defined by distinct stromal cell-related gene expression patterns. By taking a closer look at those stromal clusters, the investigators were able to start teasing out some of the microenvironment changes that may impact tumor growth or treatment response.

In particular, the team pointed to a transcriptomic cluster marked by inflammatory cancer-associated fibroblast cells in the stroma that express higher-than-usual levels of the T immune cell-staunching CXCL12 chemokine, which may provide an avenue for boosting immunotherapy-based treatments in this TNBC subtype.

"Our findings suggest that there is significant crosstalk between the immune system and stromal cells, which were generally thought to have only a structural role in cancers," Swarbrick said in a statement, noting that "T cells will be more susceptible to activation and more likely to attack the cancer" in response to immunotherapy treatments if the T cell-inflammatory cancer-associated fibroblast interactions that dampen down T cell activity can be upended.

In an effort to find previously unappreciated treatment options, the team used scRNA-seq to profile more than 6,000 transcripts apiece in 24,271 single cells from five primary TNBC cases, identifying four stromal cell populations: a cancer-associated fibroblast sub-population marked by myofibroblast or growth factor/immunomodulatory features, and sub-populations of perivascular-like stromal cells with differentiated or immature characteristics.

After a series of follow-up signaling prediction analyses, the authors suggested that "these stromal states have distinct morphologies, spatial relationships, and functional properties in regulating the extracellular matrix." Moreover, they noted that the TNBC data on hand hinted that "stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules."

Even so, they cautioned that still more transcriptional data is needed to distinguish between the stromal cell features found in TNBC and other cancer subtypes compared to those present in support cells in cancer-free breast tissues.